Inhibitory effect of citrus 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone on 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumor promotion in mice

Abstract

5-Hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-OH-HxMF), a polymethoxyflavone, is found exclusively in the Citrus genus, particularly in the peels of sweet orange. Herein, we report the first investigation of the inhibitory effects of 5-OH-HxMF on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in mouse skin. We found that the topical application of 5-OH-HxMF can effectively inhibit the transcriptional activation of iNOS and COX-2 mRNA and protein in mouse skin stimulated by TPA. Pre-treatment with 5-OH-HxMF resulted in the reduction of TPA-induced nuclear translocation of nuclear factor-kappaB (NF-kappaB) subunit and DNA binding by blocking phosphorylation of inhibitor kappaB (IkappaB) alpha and p65 and subsequent degradation of IkappaBalpha. In addition, 5-OH-HxMF can inhibit TPA-induced phosphorylation and nuclear translocation of the signal transducer and activator of transcription-3. Moreover, 5-OH-HxMF can suppress TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt, which are upstream of NF-kappaB. We also found that 5-OH-HxMF significantly inhibited TPA-induced mouse skin inflammation by decreasing inflammatory parameters. Furthermore, 5-OH-HxMF significantly inhibited 7,12-dimethylbenz[a]anthracene/TPA-induced skin tumor formation by reducing the tumor incidence and tumor multiplicity of papillomas at 20 weeks. Therefore, all these results revealed for the first time that 5-OH-HxMF is an effective antitumor agent and its inhibitory effect is through the down-regulation of inflammatory iNOS and COX-2 gene expression in mouse skin, suggesting that 5-OH-HxMF is a novel functional agent capable of preventing inflammation-associated tumorigenesis.

Chemoprevention of colonic tumorigenesis by dietary hydroxylated polymethoxyflavones in azoxymethane‐treated mice

“…However, the mechanisms underlying its actions have yet to be well characterized. In addition, recent studies have shown that some hydroxylated PMFs have more potent biological activities including anti-cancer and anti-inflammatory activities than their PMF counterparts [21,24,25]. This information indicated the hydroxylated PMFs may possess greater potency for colon cancer chemoprevention.…”

“…Among these, polymethoxyflavones (PMFs), particularly in the peel of sweet oranges (Citrus sinensis) and mandarin oranges (Citrus reticulate), have been demonstrated to have various biological activities including anti-carcinogenic, anti-inflammatory and antitumor activities [19,20]. Our pervious studies also reported that 5-hydroxy- 3,6,7,8,3 0 ,4 0 -hexamethoxyflavone isolated from sweet orange peel extract shows the inhibitory effects against TPA-induced skin inflammation and tumor promotion in mice [21]. The most known and studied citrus PMF, nobiletin, has been reported in inhibition of AOMinduced colonic ACF formation in male F344 rats [22,23].…”

Tetramethyl-O-scutellarin isolated from peels of immature Shiranuhi fruit exhibits anti-inflammatory effects on LPSinduced RAW264.7 cells

“…Phytochemical studies of Citrus peels have led to identifying some metabolites including flavonoids [2,3], limonoids [4,5], and coumarins [6]. Polymethoxyflavones (PMFs) have attracted considerable attention as bioactive constituents in Citrus peels [2,7] owing to their antiinflammatory [8], anticarcinogenic [9], and antiatherogenic properties [10]. Besides, antioxidant [11,12] and antitumor properties [13] were also identified from the flavonoids of Citrus genus.…”

Linear Programming Formulation of a Dairy Drink Made of Cocoa, Coffee and Orange By-Products

“…The major polyphenols present in orange peel are flavanone glycosides, polymethoxylated flavone aglycons, flavone glycosides and C-glycosylated flavones (Sawalha et al, 2009) and health benefit such as anti -inflammatory, anticarcinogenic, anti-viral, antioxidant, anti-thrombogenic and anti-atherogenic properties has been reported it (Middleton et al, 2000;Whitman et al, 2005;Lai et al, 2007;Li et al, 2009). TPC reported for coffee silverskin was higher that the value found in the literature 0.17 mg EGA/g sample (Jiménez-Zamora et al, 2015).…”